Retinoblastoma

Definition

Etiology

Retinoblastoma arises due to mutation of the retinoblastoma tumor-suppressor gene on chromosome 13q14. There are two forms, hereditary and non-hereditary.

In the hereditary setting, this mutation is present in one allele of all germ line cells. According to the “two-hit” hypothesis, an additional spontaneous mutation of the remaining allele must develop in at least one somatic cell of the retina.

The non-hereditary form arises from spontaneous mutation affecting both alleles in a somatic cell of the retina.

Epidemiology

Retinoblastoma is a rare childhood cancer, occurring in approximately 1 in 15,000 to 1 in 16,600 live births in the US with 300-350 new cases diagnosed annually. Although some cases have been reported in adults, most tumor affect children under two years of age, usually (75%) affecting one eye due to non-hereditary spontaneous mutation.

Bilateral disease is generally heritable in an autosomal dominant manner. Associated with the heritable form is a second form of cancer (51%), most commonly osteogenic and soft tissue sarcoma.

Symptoms

The most common presenting feature in the US is leukocoria (an absence of the red reflex of the eye). Strabismus (misalignment of the eyes) is the second most common presenting feature. Testing for the red reflex using an ophthalmoscope and observing extra-ocular muscle movements are therefore indispensable parts of the physical examination in the pediatric population. In developing countries, retinoblastoma often goes unrecognized until the patient presents with an enlarged eye with locally invasive disease.

Differential Diagnosis

Toxocara endophthalmitis which results from infestation with dog, cat, or fox roundworm (Toxocara spp.); migration of the larvae to the eye can cause leukocoria and strabismus.

Persistent Hyperplastic Primary Viterous (PHPV). In PHPV, the primary vitreous used in formation of the eye during fetal development remains in the eye upon birth and is hazy and scarred.

Coats’ disease, a very rare congenital, nonhereditary eye disorder characterized by abnormal development of blood vessels behind the retina; it most commonly presents with leukocoria secondary to glaucoma, cataracts, and/or retinal detachment.

Retinopathy of prematurity, thought to be caused by disorganized growth of retinal blood vessels secondary to hypoxia and oxygen toxicity, which may result in scarring and retinal detachment.

Congenital cataracts which may be inherited, idiopathic, or a result of congenital rubella infection and often present with leukocoria.

Glaucoma which can present with haziness of the vitreous.

Coloboma, a hole in one of the structures of the eye, can present with leukocoria and strabismus.

Diagnostic Tests

The most important confirmatory test is ophthalmoscopic examination under anesthesia that permits visualization of the tumor and the retina. This may be supplemented with U/S, CT, or MRI, especially when the physician suspects optic nerve involvement or “trilateral retinoblastoma” (involvement of both eyes plus the pineal gland; 3% of all retinoblastoma cases).

In the event that metastasis is suspected due to complaints such as vomiting, weight loss, proptosis, and/or a focal neurological deficit, a full work up should be pursued including bone marrow examination, spinal fluid analysis and bone scan.

In theory, biopsy is the only way to absolutely confirm retinoblastoma. However, retinoblastoma is a rare tumor in that a tissue sample is routinely not obtained to establish diagnosis, principally because the radiographic and physical findings are typical but also from an urge to avoid extraocular seeding, a situation that clearly worsens prognosis.

Treatment

There are several treatment modalities for retinoblastoma. Commonly, combination therapy is utilized to optimize individualized care.

External beam radiation therapy (EBRT) was once widely used as its success rate at eye preservation exceeded 85%; however, sequelae of radiation including recurrence of tumor and cosmetic defects have rendered this a salvage therapy. Newer modalities including Intensity-Modulated Radiation Therapy (IMRT) and three-dimensional (3D) conformal radiation therapy are emerging as potentially useful radiation techniques with minimal collateral damage. Perhaps the most promising new therapy is brachytherapy, utilizing radioactive plaques focused specifically on the small area of tumor tissue.

Systemic chemotherapy includes agents such as carboplatin, vincristine, and etoposide. This is useful in reducing tumor size, but generally requires adjuvant measures such as brachytherapy.

Enucleation (removal of the eye) unfortunately remains the treatment of choice when the tumor has seeded or is very large. Enucleation has declined as a practice in developed countries over the last several decades as vision-sparing therapies have come to the fore.

Intra-arterial chemotherapy is a technique that has been used in other childhood tumors, particularly those of the brain, and involves injection of chemotherapy into specific, local arterial systems. The advantage of intra-arterial chemotherapy is the focal delivery of chemotherapy with presumed minimal systemic side effects, but risks include cerebral hemorrhage, thrombosis, embolism, and infection; arterial endothelial toxicity, stenosis, and occlusion; and globe loss. This treatment modality has only recently been applied to retinoblastoma and advantages of its use as solo (or combination) therapy have largely yet to be elucidated, but appear promising in early studies.

Prognosis

Retinoblastoma confined within the eye has excellent prognosis with reported survival rates of above 90%. When this disease goes undetected, as is often the case in developing countries, tumor often spills from the sclera into the orbit or beyond the optic nerve leading to seeding in the vitreous cavity or extension into the subretinal space, thereby decreasing survival rates to around 50%.